The Roman general Drusus founded the Roman stronghold of castrum Moguntiacum, the precursor to Mainz, in 13 BC. As related by Suetonius the existence of Moguntiacum is well established by four years later (the account of the death and funeral of Nero Claudius Drusus), though several other theories suggest the site may have been established earlier.

Although the city is situated opposite the mouth of the Main river, the name of Mainz is not from Main, the similarity being perhaps due to diachronic analogy. Main is from Latin Menus, the name the Romans used for the river. Linguistic analysis of the many forms of the name "Mainz" have taken on, make it clear that it is a simplification of Moguntiacum.

The name appears to be Celtic and ultimately it is from the Celtic. However, it also had become Roman and was selected by the Romans with a special significance. The Roman soldiers defending Gallia had adopted the Gallic god Mogons (Mogounus, Moguns, Mogonino), for the meaning of which etymology offers two basic options: "the great one", similar to Latin magnus, which was used in aggrandizing names such as Alexander magnus, "Alexander the Great" and Pompeius magnus, "Pompey the great", or the god of "might" personified as it appears in young servitors of any type whether of noble or ignoble birth.

To name the fort after this particular god was an ideological statement. It was placed in the territory of the Vangiones, a formerly Germanic tribe now Celticised and working for the Romans. Their capital was at Worms on the same side of the Rhine not far to the south. Dedications of their troops serving in Britain mention the god frequently. Germania Superior was a geographical gateway between Gaul and Germany. The Romans were saying in essence by placing the fort here and naming it that "You barbarians shall not pass into the civilized and international state because the might of its youth inspired by its ancient god will stop you." If the barbarians needed any example, the previous fate of the Vangiones, who had come as conquerors and were conquered, was before them.

Moguntiacum was an important military town throughout Roman times, probably due to its strategic position at the confluence of the Main and the Rhine. The town of Moguntiacus grew up between the fort and the river. The castrum was the base of Legio XIV Gemina and XVI Gallica (9–43 AD), Legion XXII Pia Fidelis Primagenia, IV Macedonica (43–70), I Adiutrix (70-88), XXI Rapax (70-89), and XIV Gemina (70–92), among others. Mainz was also the base of a Roman river fleet (the remains of Roman patrol boats and cargo barges from about 375/6 were discovered in 1982 and may now be viewed in the Museum für Antike Schifffahrt). The city was the provincial capital of Germania Superior, and had an important funeral monument dedicated to Drusus, to which people made pilgrimages for an annual festival from as far away as Lyon. Among the famous buildings were the largest theatre north of the Alps and a bridge across the Rhine. Alamanni forces under Rando sacked the city in 368.

In last days of 406, the Siling and Asding Vandals, the Suebi, the Alans, and other Germanic tribes took advantage of the rare freezing of the Rhine to cross the river at Mainz and overwhelm the Roman defenses. Christian chronicles relate that the bishop, Aureus, was put to death by the Alamannian Crocus. The way was open to the sack of Trier and the invasion of Gaul. This event is familiar to many from the historical novel, Eagle in the Snow, by Wallace Breem.

After the fall of the Roman Empire in 476 CE, the Franks under the rule of Clovis I gained control over Western Europe by the year 496. Mainz, in its strategic position, became one of the bases of the Frankish kingdom. Mainz had sheltered a Christian community long before the conversion of Clovis. His successor Dagobert reinforced the walls of Mainz and made it one of his seats.